γ-Functionalization of α,β-Unsaturated Nitrile in Mild Condition: Versatile Synthesis of 4-Aryl-2-Bromopyridines

Article abstract of DOI:10.1002/adsc.201901002

This report describes the synthesis of 4-aryl-2-halopyridines via γ-functionalization of α,β-unsaturated nitriles, which were obtained by the HWE reaction with the corresponding ketones. The key features of our methods involve a conjugated γ-enamine formation of α,β-unsaturated nitrile (enamino nitrile), followed by consecutive intramolecular cyclization, resulting in heteroaromatic compounds like 2-halopyridines, α-pyrone, etc.

Full text of DOI:10.1002/adsc.201901002

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DOI: 10.1002/adsc.201901002
Very Important Publication
γ-Functionalization of α,β-Unsaturated Nitrile in Mild Condition:
Versatile Synthesis of 4-Aryl-2-Bromopyridines
Jaeuk Sim,a Mayavan Viji,a Jeongtae Rhee,a Hyeju Jo,a Suk Joon Cho,a, b
Yunjeong Park,a Seung-Yong Seo,c Kwan-Young Jung,b Heesoon Lee,a,* and
Jae-Kyung Junga,*
a
College of Pharmacy and Medicinal Research Center (MRC), Chungbuk National University, Cheongju 28160, Republic of
Korea
Tel.: +82-43-261-2635
fax: +82-43-268-2732
E-mail: medchem@chungbuk.ac.kr; orgjkjung@chungbuk.ac.kr
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea
College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Republic of Korea
b
c
Manuscript received: August 12, 2019; Revised manuscript received: September 5, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201901002
chemistry,[6] and so on.[7–9] Consequently, tremendous
efforts have been made on the synthesis of functional-
Abstract: This report describes the synthesis of 4-
aryl-2-halopyridines via γ-functionalization of α,β-
unsaturated nitriles, which were obtained by the
HWE reaction with the corresponding ketones. The
key features of our methods involve a conjugated γ-
enamine formation of α,β-unsaturated nitrile (enam-
ino nitrile), followed by consecutive intramolecular
ized pyridines by several groups over the past few
decades.[10]
The synthesis of halide-containing pyridine is one
of the most fascinating phenomena, mainly due to their
interesting characteristics and potential for further
functionalization. In particular, the synthesis of 2-
cyclization, resulting in heteroaromatic compounds
halopyridine has been important for medicinal
like 2-halopyridines, α-pyrone, etc.
chemistry purposes.[11]
In this context, several groups were able to achieve
synthesis of the vinylogus enamino malononitriles
Keywords: γ-functionalization; 2-halopyridine; α-
pyrone; α,β-unsaturated nitrile; vinylogus enaminoni-
from alkylidenemalononitrile, which were easily trans-
trile
formed into the desired 2-bromonicotinonitriles after
sequential reactions (Scheme 1A, X=Br).[12,13] Even
though much progress has been achieved, two EWG
groups were crucial to obtain the requisite precursor
for designated cyclization in previously described
Introduction
methods.[12–14] Moreover, removal of residual nitrile
Pyridine containing heterocyclic compounds receive proved to be very difficult. During the course of our
significant attentions because of their privileged role in continuing studies directed toward the synthesis of
various biological activities, and their presence in potent inhibitors of melanogenesis,[15] we have been
pharmaceuticals and various important molecules.[1] interested in the versatile synthesis of CGA (chloro-
For example, they are present in niacin (vitamin B3), genic acid) derivatives 4 possessing pyridine moiety
pyridoxine (vitamin B6), nicotine, etc.[2] From a (Scheme 2). However, it was concluded that all
pharmaceutical perspective, pyridines have been at the attempts to remove unnecessary nitrile group of the
forefront of drug development such as atazanavir for cyclized product 5 failed.
HIV, and imatinib mesylate for chronic myelogenous
Thus, it was necessary to devise a γ-functionaliza-
leukemia, etc,.[3] In addition, this moieties are also used tion of the single-activated substrate (e.g 1, Sche-
as chelating agents in coordination chemistry;[4] as me 1B) rather than that of the double-activated
catalysts, directing groups, and bases in organic substrate (e.g. 1q). To the best of our knowledge,
chemistry;[5] as herbicides and insecticides in agro- synthetic methods for enamino nitriles with just one
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Scheme 1. Previous work and our approach for synthesis of 2-bromopyridine.
Scheme 2. Our retrosynthetic representation for synthesis of 4-aryl-2-amino pyridine derivatives.
EWG have not been reported (Scheme 1).[16] Herein, active electrophile species. (see the mechanism,
°
we describe our efforts to develop γ-functionalization Scheme 5). The yield increased to 55% at 120 C under
of α,β-unsaturated nitriles. Salient features of our neat conditions after 2 h. Switching conditions from
present method are an efficient γ-enamine formation of neat to DMSO solvent showed superior performance
single-activated α,β-unsaturated nitriles, followed by and the highest yield of 97% was observed in just
intramolecular cyclization using a halogen source.
20 min (entry 6) mainly due to the increased solubility
of acetate in DMSO. Screening of various amount of
additive or other solvents resulted in inferior outcomes
and took longer reaction time to complete (entries 7–
Result and Discussion
The starting material 1i was easily obtained from the 10). With other acetate sources, the reactions didn’t
acetophenone via HWE reaction with corresponding show any significant improvement on the yields. For
phosphonate in high yield as a E/Z mixture (see S.I). example, when we used CsOAc, NaOAc, KOAc, or
With the key substrate for further transformation in LiOAc instead of NH4OAc, they gave the similar
hands, we attempted to explore the optimal reaction yields (52~60%, entry 11). We also screened different
condition (Table 1). We used alkylidene nitrile 1i ammonium additives and notably, ammonium
(1.0 equiv.) and DMFÀ DMA (N,N-dimethylformamide carbonate gave comparable yield of 2i at 95%, while
dimethyl acetal, 5.0 equiv.) as an initial condition. using ammonium chloride and sodium carbonate led to
When we performed the reaction at room temperature, a dramatic decrease in yields (entries 12–14); suggest-
without any additives, no enamino nitrile 2i was ing that both ammonium and acetate ions could be
observed, while we were delighted to obtain 39% yield essential for this transformation.
[17]
°
at 120 C after 24 h (entry 1).
We next attempted
With the optimal reaction condition for the γ-
Mcquade’s reaction conditions (Ac2O, DCM),[13] which enamine formation in hands, we next attempted to
did not afford the desired product (entry 2). Later, to explore intramolecular cyclization. On the basis of
activate nitrile and/or DMFÀ DMA we used acid or extensive experimentation, it was eventually concluded
base as an additive, which proved to be not helpful that using acetyl bromide as a bromide source in EA:
(entry 3).
H2O (3:1) was most effective, in terms of yield (84%
Delightfully, the reaction with ammonium acetate at yield, see S.I). Therefore, the described conditions
room temperature afforded the desired enamine 2i in were used to further explore the scope of the substrates
43% yield (entry 4). We assumed that the acetate ion (Table 2). As expected, when we applied optimized
could efficiently activate DMFÀ DMA to generate the conditions to various substrates possessing both elec-
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and afforded the products in good yields (3e–f).
Methylenedioxy and methyl sulfide also delivered, the
bromo pyridines in excellent yields (3g–h). Next, we
tested the halogen substituted acetophenones, which
were perfectly tolerated and afforded excellent yields
(3i–j). We concluded that the electron withdrawing
groups had no significant negative influence on this
reaction as we obtained very good yields (3k–m).
Moreover, 2-acetylnaphthalene afforded product 3n
in high yields. Acetyl thiophene also reacted with this
condition and rendered the expected product 3o in
66% yield. Importantly, we synthesized 2-bromonicoti-
no nitrile derivatives by modification of SM. 1-
Cyanoacetophenone after three consecutive reactions
provided 3p in 74% yield. On the other hand, all
substrate (1p, 1q and 1s) possessing active meth-
ylidene proceeded effectively with our optimized
condition afforded the desired products (3p, 3q[13c] and
3s) in comparable yield.[18] This same method was
amenable with α-tetralone, and the initially synthesized
dinitrile was successfully converted into the corre-
sponding product 3r[13c] in 53% yield. Notably, DCM
in place of DMSO at room temperature also gave 3p,
3q and 3s in good yields. However, alkyl and aryl
substrates at the γ-position of 1 showed the less
favorable results. For example, propiophenone did not
provide the desired enamine product, while 2-phenyl-
acetophenone gave low yield of the corresponding
enamine in less than 20% yield.
Table 1. Optimization of Reaction Conditions for the Enamine
.
[a]
Entry Additive
(1.2 equiv.)
Solvent Temp.
Time
(h)
Yield
(%)[b]
°
( C)
1
2
–
–
120
24
39
Ac2O[c]
DCM
RT/reflux 24
NR
NR
43
3
4
5
6
7
8
9
10
11
12
13
14
Acid or Base[d]
NH4OAc
NH4OAc
NH4OAc
NH4OAc[c]
NH4OAc[e]
NH4OAc
NH4OAc
Other acetates DMSO 120
NH4Cl
(NH4)2CO3
Na2CO3
–
–
–
120
RT
120
24
24 h
2 h
20min 97
24
2
24
24
3
24
3
55
DMSO 120
DMSO 120
DMSO 120
60
80
48
59
52~60
14
95
DMF
120
Benzene 120
DMSO 120
DMSO 120
DMSO 120
3
47
[a] Reaction conditions: 1i (0.2 mmol, 1.0 equiv.), DMFÀ DMA
(5.0 equiv.), solvent (1.0 M).
[b] Determined by GC using mesitylene as an internal standard.
[c] 20 mol% additive was used,
[d] Acetic acid, NaOMe, DBU and K2CO3.
[e] 3.0 equiv. of additive was used, RT=Room Temperature,
NR=No Reaction.
We have successfully isolated both E and Z isomer
alkylidene nitrile of 1i after the HWE reaction, and did
separate enamino nitrile synthesis, which fortunately
provided 2i as E/Z mixture (Scheme 3). The reaction
tron donating and withdrawing groups in the acetophe- with bromine provided dibromo derivative 7 in 45%,
nones, they were well tolerated and delivered the and using our optimized condition delivered the
corresponding products in good to high yields (Ta- expected product 3i in 84% yield.
ble 2). The substrates containing alkyl in ortho, meta
To gain a deep insight into the reaction pathway, we
and para positions of the aromatic ring afforded the have done several control experiments. Considering
expected products in very high yields (Table 2, 3b–d). that the reaction of 1i with NaOMe did not give any
Similarly, methoxy substituents proceeded smoothly conversion under neat conditions (Table 1, entry 3), we
Scheme 3. Control Experiments A.
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[b]
Table 2. Synthesis of 2-Bromopyridine Derivatives [a]
, .
[a] Reaction condition: see supporting information for details.
[b] Isolated yield after two steps.
[c] Only changes using solvent DCM.
first attempted the same reaction in DMSO to afford observed at 30%, this may be due to the low
the desire product 2i in 30% yield. We surmised that stabilization ability of NaOMe than NH4OAc. Finally,
DMFÀ DMA initially dissociates into both alkoxyimi- when D2O was used as a proton source to find out
nium cation and methoxide ion, which acts as a base to whether the reaction pathway is an ene type or an
abstract γ-hydrogen. The product formation is mainly enolate type reaction, mixture of products containing
dependent on alkoxyiminium cation’s stabilization. For deuterium exchanged products 1i–d was obtained in
instance, when the reaction was carried out with 70% yield, along with 30% of the desired product 2i.
NaOMe instead of NH4OAc, diminished yield was The above results clearly demonstrate that both are
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Scheme 4. Control Experiments B.
Scheme 5. Plausible Reaction Mechanism.
possible ways to produce the product. Moreover, this deliver D. Intermediate D subsequently eliminate
also reveals that both of DMFÀ DMA and NH4OAc are methanol affords enaminonitrile E. It is then an intra-
very essential for this reaction, and without these, no molecular Pinner cyclization with in-situ generated
deuterated product 1i–d is obtained.
HBr gave the final 2-bromopyridine F.[13]
Based on the above experiments we depict a
In the pathway B, extended conjugated enolate B’
plausible mechanism in Scheme 5. In the reaction was induced by the methoxide obtained from
pathway A, nitrile group of the A could be activated DMFÀ DMA. B’ then attacks the iminium ion C to
by ammonium ion and methoxide evolved from produce D.
DMFÀ DMA was initiate base-catalyzed isomerization
To check the feasibility of this reaction condition,
to give both Ene isomer B as well as iminium ion C. we also tested this with gram scale synthesis which
Much reactive isomer B then could react with C to produced 81% overall yields of 2-bromo pyridine 3i
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Scheme 6. Gram-Scale Reaction and Applications.
Experimental Section
after two steps (Scheme 6). Meanwhile we introduced
t-butylester 8 as EWG instead of CN, which converted
into α-pyrone 9 in good yield. The reaction scope was
extended to the synthesis of 2-chloro pyridine 10. At
the final intramolecular cyclization, using acetyl
chloride instead of acetyl bromide provided the above
product in high yield.[19] Finally, the synthesized
bromoÀ pyridine 3c successfully underwent Suzuki-
Miyaura coupling and afforded the corresponding
coupling product 12 with excellent yield of 95%.
General procedure for the 1st step: To a solution of substituted
α,β-unsaturated nitriles 1a–s (0.65 mmol, 1.0 equiv.) and
NH4OAc (0.78 mmol, 1.2 equiv.) in DMSO (0.65 mL),
DMFÀ DMA (3.25 mmol, 5.0 equiv.) was added. The resulting
°
reaction mixture was heated under 120 C until reaction was
completed as monitored by TLC. The reaction mixture was
subsequently allowed to cool to room temperature, diluted with
water and extracted with chloroform. The combined organic
layers were washed with a saturated NaCl solution, dried over
anhydrous MgSO4 and evaporated. The resulting enamines 2
were taken to next reaction without any further purification.
Conclusion
General procedure for the 2nd step: To a solution of enamines
2 (0.65 mmol, 1.0 equiv.) in ethyl acetate (1.3 mL) and H2O
(0.4 mL), AcBr (13.0 mmol, 20.0 equiv.) was added slowly
In conclusion, we have developed a novel method for
4-aryl-2-halopyridines by employing γ-enamine forma-
tion of α,β-unsaturated nitriles, followed by Pinner
cyclization. Compared with the previous reports which
used the activated alkylidene dinitriles, this method
offers several advantages like mild reaction condition,
simplicity of operation and atom-ecomomic process.
We also demonstrated that this protocol can be applied
to α-pyrone synthesis, as well as gram-scale reaction.
Efforts toward various γ-functionalization of α,β-
unsaturated EWGs with other electrophiles are cur-
rently underway, and a full account of application to
the heteroaromatic compounds will be reported in due
course.
°
drop wise at 0 C in ice bath. The ice bath was removed and the
resulting mixture was warmed up to room temperature and
stirred for 4 hours. After the reaction was complete as
monitored by TLC, it was quenched with a saturated aqueous
solution of NaHCO3. After separation of the organic layer, the
resulting mixture was extracted with ethyl acetate and the
combined organic phase was dried over anhydrous MgSO4.
After filtration and evaporation of the solvent, the crude residue
was purified by chromatography (silica gel, 4–10% ethyl acetate
in hexanes) to afford the 2-bromopyridine derivatives 3.
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Acknowledgements
This work was supported by the National Research Foundation
of Korea grants funded by the Korea Government (MSIP)
(MRC 2017R1A5A2015541, and Basic Science Research Pro-
gram 2017R1D1A1B03) and the International Science and
Business Belt Program through the Ministry of Science, ICT
and Future Planning (2017K000490).
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Adv. Synth. Catal. 2019, 361, 1–9
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UPDATES
γ-Functionalization of α,β-Unsaturated Nitrile in Mild
Condition: Versatile Synthesis of 4-Aryl-2-Bromopyridines
Adv. Synth. Catal. 2019, 361, 1–9
J. Sim, M. Viji, J. Rhee, H. Jo, S. J. Cho, Y. Park, S.-Y. Seo,
K.-Y. Jung, H. Lee*, J.-K. Jung*